How does smoking reduce the risk of preeclampsia?

Although smoking during pregnancy may lead to many adverse effects, such as fetal growth restriction, placental abruption, stillbirth, and preterm labor, smoking is the only environmental exposure known to consistently reduce the risk of preeclampsia and gestational hypertension.1 The article by Wikström et al2 is a major step forward in understanding this protective effect. Using data from the Swedish Medical Birth Register in a large epidemiological study of 600 000 Nordic women, the authors conclude that use of Swedish snuff, a smokeless tobacco, did not reduce the risk of preeclampsia and gestational hypertension but that tobacco, when smoked, did. They infer that combustion products of tobacco, such as carbon monoxide (CO), protect against preeclampsia but that constituents of tobacco, such as nicotine, do not. The data strengthen and extend results of a previous smaller study using the Swedish Medical Birth Register, which had reported a similar association.3 Although snuff use did not reduce the risk of mild or severe preeclampsia, preeclampsia that began before or after 37 weeks of gestation, or preeclampsia with or without delivery of a small for gestational age (SGA) infant or stillbirth, smoking reduced the risk of all categories of preeclampsia except for preeclampsia with an SGA infant or stillbirth. Of considerable interest, using data from women who changed their tobacco habits at gestational weeks 30 to 32 from those reported at the first antenatal visit (usually before 15 weeks of gestation), Wikström et al2 found that women who had reported smoking at the first antenatal visit but no use of tobacco at 30 to 32 weeks did not have reduced risk of preeclampsia or gestational hypertension compared with tobacco nonusers, whereas women who reported no use of tobacco at the first antenatal visit but smoking at 30 to 32 weeks did. This implies that smoking during the second half of pregnancy is necessary for reducing the risk of preeclampsia or gestational hypertension. Our understanding of the pathogenesis of preeclampsia has undergone a major revolution in the last decade. It is now believed that the clinical phenotype of preeclampsia may be mediated by a circulating antiangiogenic state largely attributed to placental overproduction of soluble fms-like tyrosine kinase 1 (sFlt1), an endogenous vascular endothelial growth factor signaling inhibitor, and soluble endoglin (sEng), a transforming growth factorsignaling inhibitor.4 The etiology of these alterations has been the subject of intense debate, with a number of hypotheses advanced, including oxidative stress, altered immunologic factors, insulin resistance, and enhanced angiotensin II signaling. Can we explain the effects of smoking reported by Wikström et al2 in terms of our new understanding of the pathogenesis of preeclampsia? First of all, smoking during pregnancy has been associated with lower circulating concentrations of the antiangiogenic proteins, sFlt1 and sEng, and higher concentrations of the proangiogenic protein, placental growth factor.5,6 Because preeclampsia usually begins after the middle of the second trimester of pregnancy coincident with substantial rises in circulating sFlt1 and sEng, it is not entirely surprising why smoking during the latter half of pregnancy has the greatest benefit. Wikström et al2 report that the protective effect of smoking appears to be less for the more severe forms of preeclampsia, preterm preeclampsia and preeclampsia with an SGA infant or stillbirth. Moreover, although there is a dose-response relationship between smoking and risk for the mild forms of preeclampsia (term preeclampsia, preeclampsia without SGA or stillbirth, or mild preeclampsia), there is no such relationship for the severe forms (preterm preeclampsia, preeclampsia with SGA or stillbirth, or severe preeclampsia). It should be noted that preeclampsia with SGA in this study is preeclampsia with severe SGA ( 2.5%), and it may be associated with much greater alterations of antiangiogenic proteins than preeclampsia with SGA defined as 10.0%. We believe that every woman has a threshold for angiogenic imbalance, which, when crossed, will lead to preeclampsia. Because alterations in angiogenic proteins are greater in severe forms of preeclampsia, it should take more of a reduction in angiogenic factor concentrations to bring them below threshold and to prevent onset of preeclampsia. Thus, a given amount of smoking will afford less protection to women destined to develop preterm preeclampsia or preeclampsia with an SGA infant or stillbirth than to women who will develop mild or term preeclampsia. Cnattingius et al7 and Pipkin8 have both reported that, although smoking reduces the incidence of preeclampsia, it worsens pregnancy outcomes in smokers who develop preeclampsia. We suggest that smoking more frequently prevents preeclampsia from developing in women who would otherwise experience mild disease, thus increasing the proportion who experience severe disease and worse outcomes. Recently, Chappell et al9 have reported an association of smoking with increased risk of superimposed preeclampsia in women with chronic hyperThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Howard Hughes Medical Institute (S.A.K.), Center for Vascular Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass; Division of Epidemiology, Statistics, and Prevention Research (R.J.L.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md. Correspondence to S. Ananth Karumanchi, Beth Israel Deaconess Medical Center, 330 Brookline Ave, RN 370D, Boston, MA 02215. E-mail [email protected]; or Richard J. Levine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 6100, Room 7B03, Bethesda, MD 20892. E-mail [email protected] (Hypertension. 2010;55:1100-1101.) © 2010 American Heart Association, Inc.