Cigarette Smoking and Pregnancy II: Vascular Effects

Cigarette Smoking and Pregnancy II: Vascular Effects

Placenta (1999), 20, 273–279 CURRENT TOPIC Cigarette Smoking and Pregnancy II: Vascular Effects C. Salafiaa and K. Shiverickb a Department of Pathol...

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Placenta (1999), 20, 273–279

CURRENT TOPIC Cigarette Smoking and Pregnancy II: Vascular Effects C. Salafiaa and K. Shiverickb a

Department of Pathology, Columbia University College Medical Center, USA Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, USA Paper accepted 9 November 1998

b

The act of smoking introduces a complex set of chemicals that have a broad range of effects, both complementary and antagonistic, at various levels within the vascular tree. A general review of these systemic effects is followed by a summary of documented effects of smoking on the uterine vasculature and of relationships of smoking to pregnancy outcomes known to be associated with vascular pathology. Last, we offer a potential resolution for the apparent paradox of the seemingly ‘protective’ effect of smoking to reduce the incidence of pre-eclampsia, one of the most serious vascular complications of pregnancy. Placenta (1999), 20, 273–279  1999 W. B. Saunders Company Ltd This review will focus on the clinical manifestations of and potential mechanisms underlying smoking-associated vascular complications of pregnancy. Cigarette smoking is associated with increased risks of perinatal mortality, spontaneous abortion, abruptio placentae and intrauterine growth retardation (Raymond, Cnattinguis and Keily, 1994; Ananth, Savitz and Lutther, 1996; Andres, 1996), whereas there is a decreased risk of pre-eclampsia (Klonoff-Cohen, Ede and Savitz, 1993; Andres, 1996).

VASCULAR EFFECTS OF SMOKING Sudden cardiac death accounts for the majority of smokingrelated deaths each year in the USA (Kannel, 1981). It is no surprise, therefore, that large vessels dysfunction has been reported in smokers. Consistent changes in arterial pulse contour (decreased amplitude and duration of the diastolic wave) have been identified in long-term smokers. Such pulse contour changes are believed to reflect an abnormal structure of, or abnormal tone in, the peripheral vasculature, changing pulsatile arterial function (McVeigh et al., 1997). The pressure pulse wave reflections in the peripheral circulation arise from discontinuities in the caliber or the elastic properties along the arterial tree. Optimally, the reflected waves appear in diastole and augment coronary perfusion pressure without increasing left ventricular after-load. Diminished diastolic oscillation is an obvious finding in vessels with abnormally stiff walls; in adult smokers, this stiffness is often due to atherosclerotic plaques. Abnormal vascular anatomy could be related to several different factors, including changes in intimal structure induced by nicotine and carbon monoxide (Thomsen, 1974; Asmussen and Kjeldsen, 1975; Ribeiro et al., 1983). Abnormal platelet–vessel 0143–4004/99/040273+07 $12.00/0

wall interactions (Murray et al., 1990a) may lead to thrombosis and/or intimal-medial remodelling. The evidence of direct platelet activation in smokers is also compelling (Murray et al., 1990a), but this short-term and reversible effect may be less important than the more persistent effect (which long outlasts smoke exposure) on prostacyclin and its metabolites (Murray et al., 1990b). The effects of smoking to increase arterial uptake of atherogenic plasma proteins may set up a ‘vicious cycle’ of thrombotic injury (Born, 1994). In this regard, smoking is associated with increased circulating levels of lipid peroxidation products, factors believed to contribute to endothelial injury in, for example, chronic inflammatory disorders (Blake et al., 1985). Lapenna et al. (1995) observed no intrinsic lipid peroxidative capacity of smoke; however, when smoke interacted with ferritin, a marked iron-driven lipid peroxidation was manifest. Given the dynamic state of iron metabolism in the pregnant women, the risk of smoke-associated lipid peroxidation may be greater than in the non-pregnant state. A second process of direct endothelial injury, not mediated by thiocyanate or lipid peroxides, by smoking can also be demonstrated by increased circulating levels of von Willebrand’s factor, the release of which accompanies endothelial injury (Blann and McCollum, 1993). Increased circulating levels of von Willebrand’s factor in smokers were independent of levels of lipid peroxides, but paralleled seruim thiocyanate and nicotine levels. Neither thiocyanate nor nicotine were endothelio-toxic in vitro, except at supraphysiological levels. However, nicotine’s effects to stimulate DNA synthesis and proliferation in vascular endothelial cells in vitro (Villablanca, 1998) may be important in the genesis of the overall pathological anatomy of the systemic vasculature in chronic smokers and other secondary effects of thiocyanate and nicotine cannot be excluded.  1999 W. B. Saunders Company Ltd

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Functional alterations of the vasculature cannot be completely dissociated from structural events. Smoking is proposed to affect arterial uptake of atherogenic plasma proteins (and affect vascular structure) via increased circulating catecholamine levels (Born, 1994) which may alter vasomotor tone compounding the structural problems with abnormal function. The pharmacology of tobacco combustion products is complex not only due to the plethora of by-products, but also because agents (e.g. nicotine) may have different vascular effects at different doses [ranging from vasoconstriction to vasodilatation (Li and Duckles, 1993)]. Thus, while nicotine itself lowers prostacyclin production, carbon monoxide renders the endothelium relatively hypoxic and raises local prostacyclin levels (Effeney, 1987). Also, the effects of any one agent may be influenced by frequency of smoke exposure based upon evidence. Regular smoking appears to sensitize the peripheral vasculature to the vasoconstrictive effects of the next cigarette. When aspirin was administered to a group of smokers, a study of finger blood flow suggested that this sensitization may be mediated by reduced local endothelial prostacyclin synthesis (Goodfield, Hume and Rowell, 1990). Smoking also appears to preferentially activate certain pathways of tissue injury. In smokers, neutrophil transit through lung microvasculature is prolonged (Brown et al., 1995). An increase in neutrophil residence time in capillaries may be the first step leading to cells accumulating within the lung interstitium and the bronchoalveolar space, potentiating lung damage. Thus, activated neutrophils may be preferentially retained. Finally, smoking affects tissue revascularization and the inhibition of the angioblastic response by nicotine has been proposed to delay healing of bone grafts. Compared to placebo, nicotine-exposed bone grafts had delayed development of graft neovasculature, a reduced percentage area of neovascularization and a greater incidence of focal necrosis (Daftari et al., 1994). The evidence relating smoking to vascular dysfunction is compelling and accepted; however, understanding the precise impact of smoking on any one of the multiple variables that influence vascular function is complicated by the large range of potential vasoactive mediators in smoke and by the level of the vascular tree in which effects are studied. Overall, the net effect of smoking can be thought as producing a permanent vascular structural pathology that may be either the cause or the result of long-standing vascular functional alterations.

THE VASCULAR ANATOMIES OF PREGNANCY There are three vascular spaces unique to pregnancy: the maternal vasculature in the decidua and myometrium remodelled by invasive trophoblast; the intervillous blood space, an extravascular space bounded by the villous syncytiotrophoblast epithelium; and the fetoplacental vasculature. The uterine vasculature of a successful pregnancy reflects a remarkable adaptation of mature arteries to accommodate massive increases in flow volume, which is executed principally but not

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exclusively by the invasive endovascular cytotrophoblast. Maternal vascular remodelling finally extends to destruction of intima, media and elastica, with their replacement by an amorphous ‘fibrinoid’ material, laid down at least in part by the semi-allogeneic trophoblast. Maternal re-endothelialization of this foreign material completes the remodelling process. The intervillous space has also recently been shown to be a dynamic and frequently remodelled vascular space; the perivillous fibrin/fibrinoid, often dismissed as normal ageing changes, have been proposed to play a role in adapting the intervillous space to optimize uteroplacental perfusion (Frank et al., 1994). The fetoplacental vasculature is remarkable as a highly dynamic system extending both as a macrovascular and a microvascular structure within fetus and placenta during pregnancy.

SMOKING AND THE VASCULATURE Association with early placental vascular complications? The increased miscarriage rate among mothers who smoke (Economides and Braithwaite, 1994) may be as high as 33 per cent (Walsh, 1994). Experimental data support the hypothesis that smoking may have deleterious effects both on the placenta’s ability to implant and on the vascular adequacy of the uterine vascular environment. Jauniaux and Burton (1992) have described increased syncytial necrosis and increased thickness of the syncytio/cytotrophoblast membrane in early pregnancy in mothers who smoke. During early pregnancy, stem cells either fuse to form the syncytium or aggregate to form cell columns that first adhere to and then invade the uterus. Chorionic villous samples from early gestation obtained from women who reported cigarette use showed a marked reduction in the formation of cell columns, a defect that could not be corrected by placing them in culture (Genbacev et al., 1995). Several lines of evidence identify specific agents related to cigarette smoking as having a negative impact on early trophoblast gene expression. Chorionic villi exposed to nicotine in vitro demonstrated subsequent inhibited cell column formation and reduced invasion, apparently related to decreased cytotrophoblast synthesis and activation of the 92 kDa Type IV collagenase (Genbacev et al., 1995). Recent studies with cultured trophoblast demonstrate that oxygen tension determines whether cells proliferate or invade, with hypoxia inhibiting the ability of cytotrophoblasts to differentiate along the invasive pathway (Genbacev et al., 1997). In addition, in vitro exposure of choriocarcinoma cells to benzo(a)pyrene, a major polyaromatic hydrocarbon in cigarette smoke, significantly inhibited cell invasion of basement membrane (Zhang and Shiverick, 1997). A damaged maternal placental interface, either due to primary villous syncytial injury or to perfusion injury due to abnormal maternal uteroplacental vasculature, may explain the slight (35) elevation of mid-trimester alpha fetoprotein (AFP) levels in maternal

Salafia and Shiverick: Cigarette Smoking and Pregnancy II

serum. In addition, syncytial damage may also explain the striking (23 per cent) reduction in mid-trimester maternal serum chorionic gonadotropin levels reported in the same study of 23 668 pregnancies (Palomaki et al., 1993). Combining these observations, smoking appears to induce a generalized dysfunction of both invasive and villous trophoblasts in early pregnancy. Furthermore, angioblastic responses are reduced in smokers (Daftari et al., 1994). If this effect also extends to the endometrium, implantation efficacy might be reduced secondary to relatively deficient endometrial microvascular growth following menstrual sloughing. A final mechanism for early effects of smoking on the developing pregnancy may be related to modification of the normal maternal response to the massive decidual remodelling (and destruction) required in the early pregnant uterus. In normal early pregnancy, such intense decidual tissue remodelling results in neutrophil recruitment to foci of decidual tissue injury. Given evidence of prolonged neutrophil transit in lung microvasculature (Brown et al., 1995), a similar effect in the early decidual microvasculature near to the implanting conceptus would be predicted to be detrimental to early pregnancy and a potential mechanism contributing to increased early pregnancy loss.

Association with early fetal vascular complications? Smoking may carry an increased risk of major or minor fetal anomalies. Major anomalies reported to be associated with maternal smoking include neural tube defects (Kelsey et al., 1978; Naeye, 1978; Evans, Newcombe and Campbell, 1979; Hearey et al., 1984), congenital heart defects (Fedrick, Alberman and Goldstein, 1971; Himmelberger, Brown and Cohen, 1978; Kelsey et al., 1978), and limb reduction defects (Aro, 1983). For a simple mechanism viewpoint, these malformations could be explained by abnormal cell proliferation (with inadequate cell number to complete normal organ structure), abnormal cell migration (normal cell numbers but failure related to cell motility, intercellular adhesion, intercellular recognition), or vascular ablation (ischemic injury deforming otherwise normal structural development). If smoking affected fetal angiogenesis, a reduced capillary bed and nutritive supply could readily explain maldevelopment of fetal gross and visceral anatomy.

Association with late placental vascular complications? Recent studies have clearly confirmed shorter gestational length in pregnancies of mothers who smoke (Kistin et al., 1996), especially in older mothers (Ahluwalia, GrummerStrawn and Scanlon, 1997). The increased prematurity may not be explained by increased vaginal colonization by pathogen (Goldenberg et al., 1996). Although ‘diminished host response’ has been listed as the explanation for the relationship of maternal smoking to increased intra-amniotic infections

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(Newton, 1993), other placental complications, specifically the vascular complications of abruption and placenta previa, contribute to the increased incidence of preterm birth in smoking mothers (Meyer and Tonascia, 1977; Naeye, Harkness and Utts, 1977; Brink and Odendaal, 1987; Voight et al., 1990; Handler et al., 1994; Monica and Lilja, 1995; Chelmow, Andrew and Baker, 1996; Wong and Bauman, 1997). Others have found the risk of placenta previa in smoking mothers to be up to 2.6–4.4 times higher (Chelmow, Andrew and Baker, 1996). Placenta previa is also more likely to recur if a mother smokes (Monica and Lilja, 1995). The association of fetal growth restriction in cases with abruption has led to the proposal that smoking-associated abruption is not an acute event, but instead ‘the final event in an insidious process of placental separation’ (Voight et al., 1990). As was found in the systemic vasculature of smoking men, there is a direct relationship in pregnant women between maternal cotinine levels and uteroplacental vascular resistance as assessed by Doppler ultrasonography (Lymperopoulou et al., 1996). Radio isotope studies demonstrate a chronically reduced intervillous perfusion in smoking mothers, suggesting long-standing (possibly anatomical) modifications of the uterine or the uteroplacental vasculature (Andersen and Hermann, 1984). Chronic vascular injury in mothers who smoke may not have reached the threshold level of systemic burden required to present with clinical cardiovascular disease, but may compromise the vascular flexibility which is critical for normal pregnancy establishment and maintenance. The reported increase in platelet reactivity in pregnant smokers (Leuschen et al., 1986) may contribute to the frequency with which thrombotic uteroplacental vascular accidents such as abruption occur. Platelet-associated vascular injury, which plays a role in early atherosclerotic vascular injury, may be important in the uterine vasculature. In this respect, Naeye (1992) claims to have observed medial sclerosis of small uterine arteries. Given the pro-coagulant effects of smoking, it would be reasonable to posit that mothers who smoked and who also had phospholipid antibody syndrome would be at an even greater risk of pregnancy compromise. The literature on this subject, however, is sparse and inconclusive. A recent retrospective cohort study failed to demonstrate a conclusive interaction between smoking and the presence of phospholipid antibodies as far as increasing the frequency of recurrent arterial and/or venous thromboses (Krnic-Barrie et al., 1997). Given the lack of data on vascular-associated pregnancy compromise, caution is warranted with regard to a mother with phospholipid antibody syndrome who continues to smoke during pregnancy. The ‘vascular’ basis of placenta previa may not be as immediately obvious as that of abruption. If smoking causes a diffuse vasculopathy, reducing fundal blood flow, we might hypothesize that implantation in otherwise ‘unfavourable’ sites such as the more poorly perfused lower uterine segment and percervical endometrium could occur more commonly. In this regard, Naeye speculated that his observations of ‘medial sclerosis’ of small uterine arteries in the uteri of smoking mothers may be the anatomical basis for the Collaborative

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Perinatal Study’s findings of increased incidence of placenta previa with greater cumulative years of a woman’s smoking (Naeye, 1992). Abnormal locus of placentation is infrequently considered as a co-founder in other studies which often tend to be more purely histomorphometric analyses. In the lower uterine segment and pericervical uterus (considered ‘less preferable’ sites for implantation), there is a reduced density of spiral arteries and thinner decidua. Clinically, our experience is that histology of the type considered consistent with reduced uteroplacental perfusion or aberrant perfusion patterns is common in mal-implanted placentae, regardless of maternal smoking. A common microscopic finding in placentae of smoking mothers is decreased villous capillary volume fraction and increased thickness of the villous vasculosyncytial membrane (e.g. Burton, Palmer and Dalton, 1989). It is not known, however, whether these findings are a direct effect of maternal smoking-associated toxicity, mediated via smoking-associated vascular changes, or due to mal-implantation. Epidemiological studies support a role for maternal smoking in the induction of clinically significant uterine vascular dysfunction. Yet the incidence of pre-eclampsia, a severe maternal endothelial dysfunction, is significantly decreased in smokers. This apparent paradox may be explained by downregulation of normal endothelial mechanisms by chronic vascular pathology. We speculate that some of the vascular-associated complications associated with maternal smoking are ‘proxy outcomes’ for maternal pre-eclampsia. In other words, maternal vascular dysfunction in pregnancies complicated by smoking may merely be less likely to manifest as acute systemic hypertension, due to the existing vascular alterations.

‘PROTECTIVE’ EFFECTS OF SMOKING ON RISK OF PRE-ECLAMPSIA Pathophysiological implications Given the wide-ranging evidence of both uteroplacental and intraplacental vascular changes associated with maternal smoking, the general consensus that pre-eclampsia, the classic clinical manifestation of uteroplacental vascular pathology, is less common in mothers who smoke is striking (van der Velde and Treffers, 1985; Klonoff-Cohen, Edelstein and Savitz, 1993; Warkentin, 1994). That pre-eclampsia is less common in mothers who smoke despite an overall increase in mean maternal arterial pressure is even more surprising (Kelly and O’Connor, 1984; van der Velde and Treffers, 1985). While uteroplacental vascular pathology is commonly considered a hallmark of pre-eclampsia, we and others (Naeye, 1989; Salafia et al., 1991, 1992; Arias et al., 1993) have identified uteroplacental vascular pathology underlying non-hypertensive prematurity. We have recently shown a statistically significant increase in mean maternal admission blood pressure in spontaneous preterm birth with underlying uteroplacental vascular pathology (Salafia et al., 1998). Re-analysis of those data in preparation for this review has revealed this association to be independent of maternal smoking (unpublished results). We

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have speculated that the clinical manifestation of uteroplacental vascular pathology depends on both the uteroplacental pathology and the maternal threshhold for labour or membrane rupture, as compared to the threshhold for maternal endothelial activation. We hypothesize that maternal smoking increases the local, intrauterine vascular pathology, which causes initiation of the local, uterine responses of myometrial activation and/or membrane rupture. Furthermore, chronic smoking induces chronic and systemic endothelial events which downregulate endothelial sensitivity to the activation signals. This may be important in the genesis of pre-eclampsia. In this fashion, chronic endothelial injury caused by maternal smoking may truly ‘protect’ the mother from the cataclysmic endothelial dysfunction of pre-eclampsia. An examination of some of the primary pathophysiological mechanisms proposed to induce systemic endothelial dysfunction in pre-eclampsia is informative. (1) Impaired prostacyclin production has been implicated in the genesis of pre-eclampsia (Ylikrkala, Pekonen and Viinikka, 1986; Friedman, 1988). Regular smoking may chronically inhibit endothelial prostacyclin synthesis, habituating the endothelium to an abnormal thromboxane/prostacyclin ratio and reducing the acute response to a change in this ratio (Goodfield, Hume and Rowell, 1990). Cultured endothelial cells from the umbilical veins of mothers who smoked were significantly less able to grow and produce PGI2 than cells from non-smokers (Busacca et al., 1984). (2) Maternal metabolism in pregnancy induced hypertension resembles the main features of the ‘insulin resistance syndrome’ (Kaaja et al., 1995). Insulin sensitivity has been reported to improve after cessation of smoking in otherwise healthy men (Elaisson et al., 1997). (3) Women with pre-eclampsia demonstrate markedly elevated concentrations of triglyceride-rich lipoproteins in the circulation, a pattern which suggest parallels between pre-eclampsia and athersclerosis (Hubel et al., 1996; Sattar et al., 1997). Smokers have relative lipid intolerance and smoking cessation improves lipid profiles in otherwise healthy male smokers (Axelsen et al., 1995; Eliasson et al., 1997). (4) Lipid peroxidation is believed to be a major contributor to the pathophysiological cascade which culminates in pre-eclampsia (e.g. Garzetti et al., 1993). Smoking is associated with increased lipoprotein modification and superoxide anion, resulting in a preponderance of serum lipoproteins with enhanced atherogenicity (PechAmsellem et al., 1996; Santanam et al., 1997). Smoking cessation increases the resistance of lipoproteins to oxidation (Sasaki et al., 1997). (5) The role of nitric oxide in pre-eclampsia is complex (Sladek, Magness and Conrad, 1997). Factors in the maternal circulation in pre-eclampsia may act to increase endothelial nitric oxide (e.g. Davidge, Stranko and Roberts, 1996). Myatt and colleagues have identified increased apical syncytial immunolocalization of

Salafia and Shiverick: Cigarette Smoking and Pregnancy II

nitric oxide synthase, suggesting an increased local placental production that could be proposed to affect local uteroplacental vasculature (Ghabour et al., 1995). Smoking may reduce tissue NOS activity (Xie et al., 1997), and smoking cessation may be associated with increased exhaled nitric oxide (Robbins et al., 1997), although controversy remains (e.g. Nene et al., 1997). (6) Normal plasma volume increases in pregnancy. However, failure of plasma levels to increase has been reported in pre-eclampsia (Easterling, 1992). In smokers, there may be no change in plasma volume (Kristal-Boneh et al., 1997), but a relative polycythemia (which could clinically mimic a reduced plasma volume) is common (Ferrant, 1994). Almost point for point, the chronic endothelial and metabolic alterations associated with maternal smoking resemble the acute abnormalities seen in pre-eclampsia. We speculate that chronic smoking desensitizes the endothelium, reducing responsitivity to acute perturbations that may develop from the uteroplacental vascular injury characteristic of pre-eclampsia. This would account for smoking appearing to ‘protect’ against pre-eclampsia. We know that vascular injury does occur in the uteroplacental vasculature of smoking mothers, from the increased risk of the haemorrhagic vascular accident of abruption and preterm birth (also associated with uteroplacental vascular pathology). Abruption and preterm birth may be the only options available to the smoking mother as ‘responses’ to severe uteroplacental vascular injury. This hypothesis is consistent with the observations of Cnattinguis et al. (1997) that, while the incidence of pre-eclampsia is lower, this ‘benefit’ is effectively balanced by the increased incidence of pregnancies compromised by uteroplacental vascular pathology. Furthermore, their data suggest that, if pre-eclampsia does supervene in a smoker, the risk of poor outcome is higher than that in non-smoking pre-eclamptic mothers, consistent with what we might suspect would be underlying synergy in the local (intrauterine) pathology. Mothers in whom the total burden of ‘trigger’ for systemic endothelial dysfunction is so great as to overcome the desensitization offered by smoking could reasonably be predicted to have more severe uteroplacental disease. Warkentin (1994) offers an alternative explanation that the early onset of chronic fetal growth restriction in maternal smoking ablates or blunts a protective response of the fetoplacental unit to uteroplacental malperfusion, i.e. the production of systemic vasoconstrictive substances which could increase local uterine perfusion pressure and increase intervillous perfusion. The neutrophil effects of smoking may hold the key to understanding the predisposition of pregnancies of smoking mothers to be complicated by non-hypertensive abruption, preterm labour and/or premature membrane rupture, as opposed to pre-eclampsia. As we noted above, neutrophil

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transit through the pulmonary microvasculature in smokers is prolonged and increased neutrophil residence time in capillaries may be the first step to lung damage (Brown et al., 1995). In the pregnant uterus, neutrophil retention may tip the local cytokine balance in favour of a rapid (‘acute’) response (i.e. myometrial activation, abruption or membrane rupture) to any given tissue injury. Smoking-associated leukocyte adhesion includes formation of intravascular leukocyte–platelet aggregates, and production of lipid factors resembling plateletactivating factor (Lindell et al., 1997). These appear to induce local interleukin-8 and macrophage inflammatory protein-1 alpha secretion (Lindell et al., 1997). Both of these molecules have been implicated in the genesis of spontaneous preterm parturition (Dudley et al., 1996; Kelly, 1996). Local cytokine and other signals in pre-eclampsia may instead drive more chronic endothelial pathology, without a major local neutrophil contribution. Using routine light microscopy, the vascular lesions underlying the disparate clinical outcomes of pre-eclampsia and spontaneous prematurity cannot be distinguished. We suggest two explanations for this. (1) These lesions, although anatomically similar, have dissimilar pathophysiologies and therefore lead to different clinical outcomes by initiating different molecular cascades. (2) The difference in clinical outcome is due to the ability of the mother to respond to a single anatomical and physiological pathology. The data from associations of smoking, vascular injury and pregnancy complication would support the latter of these two options. We speculate that the maternal response to a single underlying uteroplacental pathology (and the resulting clinical complication of pregnancy) may depend on the maternal genetic and environmental background. Specific genetic variants have been associated with a predisposition to pre-eclampsia (Ward et al., 1997), supporting this model. All viscera are dependent on an intact and well-functioning circulation. The placenta is a unique organ not only from its position at the interface between the maternal uteroplacental and fetoplacental circulations, but also as a locus of intense vascular ‘activity’. The maternal vascular circuit undergoes extensive structural alterations at the arterial level, while the fetoplacental vasculature is a site of angiogenesis and vasculogenesis. The converted maternal vasculature is in effect not innervated; nor is the placenta. Vasomotor function in pregnancy may be uniquely susceptible to the chemicals found in the circulation of smokers. The effects of smoking on pregnancy outcome appear to be complex. Future studies must pay careful attention to the potentially myriad details of a smoking history, as well as potential vascular and endothelial ‘confounders’, as maternal age, parity and other environmental and genetic factors have influences on vascular function.

ACKNOWLEDGEMENTS The authors wish to acknowledge support from the National Institute of Health (K.T.S. and C.S.) and the NIEHS Superfund Basic Research Program (K.T.S.).

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